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- Mishra, A., et al.
(författare)
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Stroke genetics informs drug discovery and risk prediction across ancestries
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 611, s. 115-123
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Tidskriftsartikel (refereegranskat)abstract
- Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry(1,2). Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis(3), and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach(4), we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry(5). Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.
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| 2. |
- Jaworek, T., et al.
(författare)
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Contribution of Common Genetic Variants to Risk of Early-Onset Ischemic Stroke
- 2022
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 99:16
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives Current genome-wide association studies of ischemic stroke have focused primarily on late-onset disease. As a complement to these studies, we sought to identify the contribution of common genetic variants to risk of early-onset ischemic stroke. Methods We performed a meta-analysis of genome-wide association studies of early-onset stroke (EOS), ages 18-59 years, using individual-level data or summary statistics in 16,730 cases and 599,237 nonstroke controls obtained across 48 different studies. We further compared effect sizes at associated loci between EOS and late-onset stroke (LOS) and compared polygenic risk scores (PRS) for venous thromboembolism (VTE) between EOS and LOS. Results We observed genome-wide significant associations of EOS with 2 variants in ABO, a known stroke locus. These variants tag blood subgroups O1 and A1, and the effect sizes of both variants were significantly larger in EOS compared with LOS. The odds ratio (OR) for rs529565, tagging O1, was 0.88 (95% confidence interval [CI]: 0.85-0.91) in EOS vs 0.96 (95% CI: 0.92-1.00) in LOS, and the OR for rs635634, tagging A1, was 1.16 (1.11-1.21) for EOS vs 1.05 (0.99-1.11) in LOS; p-values for interaction = 0.001 and 0.005, respectively. Using PRSs, we observed that greater genetic risk for VTE, another prothrombotic condition, was more strongly associated with EOS compared with LOS (p = 0.008). Discussion The ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with EOS than with LOS, supporting a stronger role of prothrombotic factors in EOS.
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| 3. |
- Bonkhoff, A. K., et al.
(författare)
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Sex-specific lesion pattern of functional outcomes after stroke
- 2022
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Ingår i: Brain Communications. - : Oxford University Press (OUP). - 2632-1297. ; 4:2
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Tidskriftsartikel (refereegranskat)abstract
- Relying on neuroimaging and clinical data of 822 acute stroke patients, Bonkhoff et al. report substantially more detrimental effects of lesions in left-hemispheric posterior circulation regions on functional outcomes in women compared to men. These findings may motivate a sex-specific clinical stroke management to improve outcomes in the longer term. Stroke represents a considerable burden of disease for both men and women. However, a growing body of literature suggests clinically relevant sex differences in the underlying causes, presentations and outcomes of acute ischaemic stroke. In a recent study, we reported sex divergences in lesion topographies: specific to women, acute stroke severity was linked to lesions in the left-hemispheric posterior circulation. We here determined whether these sex-specific brain manifestations also affect long-term outcomes. We relied on 822 acute ischaemic patients [age: 64.7 (15.0) years, 39% women] originating from the multi-centre MRI-GENIE study to model unfavourable outcomes (modified Rankin Scale >2) based on acute neuroimaging data in a Bayesian hierarchical framework. Lesions encompassing bilateral subcortical nuclei and left-lateralized regions in proximity to the insula explained outcomes across men and women (area under the curve = 0.81). A pattern of left-hemispheric posterior circulation brain regions, combining left hippocampus, precuneus, fusiform and lingual gyrus, occipital pole and latero-occipital cortex, showed a substantially higher relevance in explaining functional outcomes in women compared to men [mean difference of Bayesian posterior distributions (men - women) = -0.295 (90% highest posterior density interval = -0.556 to -0.068)]. Once validated in prospective studies, our findings may motivate a sex-specific approach to clinical stroke management and hold the promise of enhancing outcomes on a population level.
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| 5. |
- Busch, K., et al.
(författare)
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Sick leave and disability pension in patients with chronic hepatitis C compared with a matched general population: a nationwide register study
- 2020
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 10:9
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Tidskriftsartikel (refereegranskat)abstract
- Objective The objective of this study was to evaluate sick leave and disability pension in patients with chronic hepatitis C virus (HCV) infection as compared with a matched general population cohort. Design Retrospective register study. Setting Nationwide in Sweden. Participants This register-based study used the Swedish National Patient Register to identify working-age patients with HCV in 2012 (n=32 021) who were diagnosed between 1999 and 2007 (n=19 362). Sick leave and disability pension data were retrieved from Statistics Sweden (1994-2012), with up to five matched individuals from the general population. Primary and secondary outcome measures The primary outcome was workdays lost due to sick leave episodes (>14 days) and disability pension overall. The secondary outcome was workdays lost per subgroup of patients with chronic HCV. Results In 2012, 14% of the HCV patients had >= 1 registered sick leave episode compared with 10% in the matched comparator cohort. For disability pension benefits, results were 30% versus 8%, respectively. Overall, in 2012, 57% of patients with HCV did not have any registered workdays lost, whereas 30% were absent >= 360 days compared with 83% and 9% in the matched cohort, respectively. The mean total number of annual workdays lost in 2012 was 126 days in the HCV patient cohort compared with 40 days in the matched general population comparator cohort. Annual days lost increased from a mean of 86 days 5 years before diagnosis to 136 days during the year of diagnosis. Conclusions These results show that Swedish HCV patients used more sick days and have a higher frequency of disability pension compared with a comparator cohort from the general Swedish population. Whether earlier diagnosis of HCV and treatment might impact work absence in Sweden warrants further investigation.
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| 10. |
- Sjödahl, Mikael, 1965-, et al.
(författare)
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In-line quality control utilizing close-range photogrammetry and a CAD-model
- 2021
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Ingår i: Engineering Research Express. - : Institute of Physics (IOP). - 2631-8695. ; 3:3
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents an overview of a measurement system that is designed for in-line shape inspection of metal sheet components in real-time utilizing pre-calibrated close-range photogrammetry and a CAD-model. The system is currently designed to measure parts thrown out on a conveyor belt that moves at about 1 m s−1 at a frequency of 0.5 Hz or less without fixturing. Detected features on the components in the camera images are used to align the CAD-model, describing the nominal shape, to the images from which required deviations are computed using photogrammetry. The measurement volume of the current system is 500 × 800 × 200 mm3 and absolute measurements are performed with an accuracy in the order of 0.1 mm. The in-line functionalities of the system have been verified at several real production sites in Sweden. In this paper, the basic components of the system are described together with a few results from real tests.
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